ADCs are highly potent and specific agents for the treatment of cancer and other conditions, where the antibody portion specifically binds to its antigen on a target cell, so that the drug can exert its cytotoxic or other therapeutic effect on the target cell, optionally after internalization. Several ADCs have been described, among them ADCs based on anti-tissue factor (anti-TF) antibodies (see, e.g., WO 2011157741 A2, which is hereby incorporated by reference in its entirety).
Like other protein pharmaceuticals, however, antibodies are prone to degradation such as oxidation, deamidation and fragmentation as well as particle and aggregate formation. To provide for an ADC pharmaceutical that is stable during transport and storage, the carriers, excipients, and/or stabilizers in the pharmaceutical formulation must therefore be carefully selected. The long-term stability of an antibody or ADC can also be improved by preparing a lyophilized or freeze-dried formulation, using excipients optimized for this purpose. Many such formulations for antibodies or ADC preparations have been described in patent literature, see, e.g. WO9704801, WO9856418, WO02011753, WO02096457, WO03009817, WO03039485, U.S. Pat. No. 8,372,396, WO2004004639, WO2004016286, WO2004055164, WO 2004071439, WO2006014965, WO2006044908 and WO2007019232.
For ADCs, there is an additional challenge in that the drug conjugation in itself can reduce the stability and alter the physicochemical properties of the antibody. For example, it has been reported that the conjugation of the drug moiety DM1 to the anti-HER2 antibody trastuzumab resulted in destabilization of the CH2 domain of the antibody (Wakankar et al, 2010). Further, cytotoxic drugs often being hydrophobic, the ADC conjugate as a whole can be less soluble than the unconjugated antibody, thus becoming more prone to aggregation, particle formation and surface adsorption. Typically, both antibody and ADC formulations include a surfactant, frequently polysorbate 20 or 80, to reduce aggregation and adsorption (see, e.g., patent literature cited supra). For example, brentuximab vedotin (trade name ADCETRIS®) is an ADC based on an anti-CD30 antibody linked to the auristatin derivative MMAE, provided as a lyophilized powder which, when reconstituted in water, contains 5 mg/mL ADC, 70 mg/mL trehalose dihydrate, 5.6 mg/mL sodium citrate dihydrate, 0.21 mg/mL citric acid monohydrate, and 0.20 mg/mL polysorbate 80, at a pH of approximately 6.6.
Accordingly, surfactants are commonly used in pharmaceutical preparations and are generally perceived as acceptable pharmaceutical ingredients. As mentioned above, surfactants are commonly used to reduce aggregate formation during antibody manufacturing and formulation (see e.g. Vásquez-Rey and Lang, 2011, Biotech, Bioeng. 108:7 p 1494). However, it is a general concern of pharmaceutical formulation to reduce the usage of non-active compounds as much as possible. This concern is both to reduce the cost of the resulting drug, but also to reduce potential unwanted effects of the excipient. For example, many surfactants are more or less toxic because of the amphiphilic nature and ability to react with biological membranes. It is not uncommon to observe LC50 of surfactants in aquatic organisms as low as 10 mg/L. Further, autooxidation or the exposure to light of polysorbates can result in the formation of hydrogen peroxide which in turn can oxidize the antibody molecule leading to a an unstable product (Kerwin, 2008; Singh et al., 2012). This not only reduces the efficacy of the ADC, but can lead to the formation of potentially harmful degradation products of the same.
Indeed, a surfactant-free formulation of a huC242-DM1 ADC containing 50 mM succinic acid, pH 6.0 and 5.0% sucrose initially described in WO2004004639 as suitable for e.g. lyophilization was later reported in WO2007019232A2 to not adequately address particle and aggregate formation.
Thus, there still remains a need for surfactant free pharmaceutical formulations for ADCs that are stable during transport and storage and substantially free of particles, aggregates and degradation products.